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CLL cells

PHILADELPHIA—A DNA-dependent protein kinase (DNA-PK) inhibitor can sensitize chronic lymphocytic leukemia (CLL) cells to chemotherapy, according to
preclinical research.

The inhibitor, NDD0004, sensitized CLL cells—even those from patients with high-risk cytogenetics—to treatment with mitoxantrone.

However, not all CLL samples were sensitive to treatment, so researchers are now trying to determine which patients might derive benefit from DNA-PK inhibitors.

Gesa Junge, a PhD student at Newcastle University in the UK, and her colleagues conducted this research and presented the results at the AACR Annual Meeting 2015 (abstract 3624*). The work was supported by AstraZeneca.

The researchers’ goal was to validate that DNA-PK inhibition is a valid approach to chemosensitization in CLL. So the team tested NU7441—a compound that inhibits DNA-PK and PI3 kinase—and NDD0004—a more selective DNA-PK inhibitor.

The team isolated CLL cells from patients’ peripheral blood, cultured the cells, and treated them with mitoxantrone and/or 1μM of NDD0004 or 1μM of NU7441.

Junge and her colleagues found that NDD0004 sensitized cells to mitoxantrone more effectively than NU7441. Sensitization was 202-fold higher with NDD004 plus mitoxantrone than with mitoxantrone alone and 69-fold higher with NU7441 plus mitoxantrone than with mitoxantrone alone (P=0.02).

However, sensitization varied between CLL samples, and the researchers have yet to determine why. Their experiments showed that variability was not a result of DNA-PK levels.

Still, the team found that CLL cells from patients with poor prognostic markers were sensitive to DNA-PK inhibition.

Sensitization with NU7441 plus mitoxantrone was 69-fold higher than mitoxantrone alone in CLL samples with del(13q), 25-fold higher in samples with del(11q), 12-fold higher in samples with TP53 mutation, and 16-fold higher in samples with ATM dysfunction.

Sensitization with NDD0004 plus mitoxantrone was 201-fold higher than mitoxantrone alone in CLL samples with del(13q), 314-fold higher in samples with del(11q), 27-fold higher in samples with TP53 mutation, and 18-fold higher in samples with ATM dysfunction.

To confirm that sensitization was a result of DNA-PK inhibition, Junge and her colleagues tested NDD0004 in an isogenic pair of DNA-PK-deficient and DNA-PK-proficient HCT116 cells. They found that HCT116 cells lacking DNA-PK were not sensitive to NDD0004, but cells with DNA-PK were sensitive.

The researchers also investigated the mechanism of NDD0004. Their results suggest the drug works by inhibiting the repair of DNA double-strand breaks.

“What we think is happening is that we are inducing DNA damage with mitoxantrone, and that gets repaired by 24 hours,” Junge said. “But if the DNA-PK inhibitor is there, the damage persists, and that seems to translate quite nicely into an apoptosis response.”

To further this research, Junge and her colleagues are hoping to identify biomarkers that can help them determine which CLL patients are likely to respond to DNA-PK inhibitors. end hematology article

*Information in the abstract differs from that presented at the meeting.


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